Natural killer cells are lymphocytes that can destroy aberrant cells such as tumor cells and virus infected cells without prior sensitization. In this respect they have a central role in the body's response to cancer. How NK cells recognize appropriate targets and avoid destruction of healthy cells is not understood. Some tumor cells are resistant to NK lysis suggesting that such cells might escape notice by this primary immune defense system. Furthermore exposure of target cells to interferon, an agent that boosts NK lytic activity, unfortunately results in increased resistance of these target cells to NK-mediate lysis. Therefore interferon treatment as a regime for therapy may have counterproductive effects. Knowing why some targets are better than others in regard to NK cell lysis would be important in diagnosing which tumors are most susceptible to therapy based on augmentation of the immune response and also in establishing appropriate treatments for modifying tumor cell sensitivity to NK activity (e.g. application of glycosylation inhibitors). Such treatments might be crucial in preventing the spread of cancer by metastasis. The characteristics that distinguish NK susceptible targets from resistant ones have not been elucidated. Preliminary results have shown that cells grown in the presence of tunicamycin (i.e. synthesis of N-linked oligosaccharides inhibited) are less susceptible to NK lysis. Also cells having high mannose-type oligosaccharides are better NK targets than cells that have complete complex-type N-linked oligosaccharides. These results suggest that the type of N-linked oligosaccharides present on target cells is important in NK mediated lysis. The experiments outlined in this proposal will (1) determine what type of N- inked oligosaccharide on targets correlates with susceptibility to lysis by either untreated or lymphokine activated NK cells; (2) demonstrate whether treatment of NK-resistant targets with specific glycosylation inhibitors enhances their sensitivity to lysis; (3) characterized the specific target cell oligosaccharide(s) involved in NK lysis; (4) determine at what step(s) in NK-target interaction the N-linked oligosaccharide on target cells is functional.